Papillomavirus infection causes persistent epithelial lesions, known as papillomas. Papillomavirus infection is also associated with the development of cervical cancer. Our laboratory has established that papillomavirus genomes and the E2 transactivator protein interact with cellular mitotic chromosomes in dividing cells. This ensures that viral genomes are properly segregated to daughter cells and are retained within the nucleus. Our aim is to elucidate the mechanisms by which the E2 proteins control the viral life cycle. Using mass spectrometry we have characterized cellular proteins that form complexes with the E2 proteins from multiple papillomaviruses. We have demonstrated that the viral E2 protein binds to active promoters in the human genome with the cellular Brd4 protein.We propose that the viral DNA is also tethered to these sites and that this prevents silencing. We have identified persistent and distinctive chromatin binding sites for the E2-Brd4 complex on human chromosomes. These novel sites persist in both interphase and mitotic cells.